Pain is a sensation felt by anybody and is an important vital signal or alarm signal.
Pain caused by injury, surgery, inflammation and the like, as well as chronic pain stemming from injury, dysfunction and the like of nerves after recovery from an injury is one of the major clinical problems. Chronic pain sometimes causes autonomic disorder, dyskinesia or mental disorder, wherein the pain itself is the cause of a different disease.
There is also known to exist pain due to sensory nerve abnormality, such as hyperalgesia associated with promotion of reaction in response to an ordinary pain stimulus, allodynia wherein pain is felt in response to a stimulus that normally causes no pain, and the like.
Analgesics are divided into central analgesic and peripheral analgesic according to the main action site thereof. Inasmuch as the cause of pain is a complicated entanglement of autonomic nerve reactions, feeling and the like, sedative, antianxiety, antidepressant, hypnotic, antispasmodic, vasodilator and the like are used as analgesic auxiliary agents.
Central analgesics are roughly divided into narcotic analgesic, anarcotic analgesic and antipyretic analgesic.
Narcotic and anarcotic opioids have been used for the treatment of sharp pain such as postoperative pain and myocardial infarction, burn and the like. These analgesics show noticeable effects resulting from a strong analgesic action combined with an action to remove fear of pain. On the other hand, narcotic analgesics accompany physical dependence and mental dependence and express withdrawal syndrome by drug dependence. Other side effects of respiratory suppresion, nausea, emesis, constipation, dysuria and the like restrict their use.
Antipyretic analgesic is effective for superficial pain, such as toothache, myalgia and the like, but is considered to be ineffective for visceralgia. Its antipyretic action is considered to focus on hypothalamus thermoregulation center, and analgesic action is mainly exerted via peripheral nerves. However, there are many unknown parts in the central action mechanism thereof. Its analgesic effect is generally weaker than that offered by narcotic and anarcotic opioids. Consequently, sharp pain is cautiously treated with narcotic and anarcotic opioids in clinical situations to the extent that causes less side effects.
Although more than 20 years have passed since the analgesic effect of morphine by intrathecal administration to human was confirmed and morphine was first applied to clinical situations, a pharmaceutical agent exceeding morphine in terms of various side effects, histotoxicity to spinal cord and the like, that accompany analgesic effect of morphine, has not been found.
Certain pain caused by injury and functional disorder of nerves and the like is resistant to analgesics currently in clinical use, such as antipyretic analgesic and narcotic analgesic, and shows no significant analgesic effect.
Thus, there reaims a demand for a safe and effective analgesic, particularly a strong analgesic free from addiction and an analgesic to treat pain caused by sensory nerve abnormality such as hyperalgesia, allodynia and the like.
Pain is caused when an algesic substance, which is released upon occurrence of tissue disorder due to nociceptive stimulus (chemical stimulus, mechanical stimulus, thermal stimulus), excites nociceptor (free nerve terminal) at the sensory nerve terminal, and the information of the pain sensation reaches the cerebral cortex and is recognized as pain. In addition, visceralgia is considered to be caused by the contraction of visceral smooth muscle, that mechanically extends and excites the sensory nerve.
Pain sensation is mostly transmitted by two kinds of thin nerve fiber Aδ and C fibers, wherein sharp mechanical stimulus conducts myelinated Aδ fiber and dull pain conducts unmyelinated C fiber. Typical algesic substance includes bradykinin, serotonin, histamine and the like, that act on nociceptor at the nerve terminal. There is a substance that encourages action of an algesic substance, like prostaglandin synthesized at the inflammation site in the peripheral tissue. Such pain afferent fiber (primary afferent fiber) forms synapse on the surface layer of dorsicornu. The primary afferent fiber excites nociceptive neuron via neurotransmitters, such as excitatory amino acid, substance P and the like, and the information is transmitted from dorsicornu to medulla oblongata, thalamus and to cerebral cortex.
Pressure and tactile sensation is mainly transmitted by thicker Aβ fiber which transmits the information from sensory nerve terminal to dorsicornu, medulla oblongata, thalamus and to cerebral cortex, like pain afferent fiber.
Opioid receptors involved in algesia exist in various parts of these spinothalamic tracts. The respiratory suppressive action, nauseant action and the like result from the action on the opioid receptor in the medulla oblongata. While opioid acts on spinal cord, medulla oblongata, thalamus and cerebral cortex to show strong analgesic effect, suppression of thalamus and cerebral cortex is not its main action. Direct suppression of opioid receptor in the dorsicornu neuron and suppression of dorsicornu neuron by descending depression via midbrain and medulla oblongata are considered to be the main action.
Tactile sensation tends to be dull upon sustained application of stimuli of the same intensity. This adaptation is unfeasible in case of pain, but sustained release of neurotransmitter by long-term stimulation of sensory nerve is considered to induce chronic pain by changing the excitatory or information transmission efficiency of the nerve cell. In addition, inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA), glycine and the like, suppress excitement of nerves upon activation of each receptor. While allodynia is considered to be partly induced by dull suppression of neurotransmission due to the stimuli repeatedly applied to the sensory nerve, the mechanism of the onset of chronic pain, hyperalgesia and allodynia has been known only to a limited degree.
As described, the sensory nerve transmission is controlled by excitatory nerve fiber and inhibitory nerve fiber in complicated relationship with each other, and many neurotransmitters involved therein have been found to exist. Hence, there are many targets used to find a pharmaceutical agent exhibiting effective analgesic action.
Following the discovery of cerebral morphine receptor in 1973, enkephalin, which is an endogenous pentapeptide having analgesic effect, was first found and isolated in 1975. There are known more than 20 kinds of morphinomimetic peptides under the category of opioid peptide, that inhibit the transmission of algesia information.
These opioids inclusive of morphine act on opioid receptor. The opioid receptor is known to include several subtypes, wherein morphine shows high affinity for μ receptor, enkephalin shows high affinity for δ receptor and dynorphin shows high affinity for κ receptor, these consisting the base thereof.
It is a long-known fact that involvement of μ receptor from among these is important for the analgesic effect and the mechanism thereof has been most elucidated. The study of withdrawal syndrome induction capability and the like of each subtype by the use of opioid antagonist has revealed that the morphine addiction is mainly attributable to the action via μ receptor.
An opioid receptor like-1 (ORL-1) receptor has high homology with opioid receptor but does not bind with conventional opioid ligands. This receptor was cloned in 1993.*1*2 In 1995, peptide consisting of 17 amino acids was isolated as endogenous ligand of ORL-1 receptor, and structurally characterized and named Nociceptin or Orphanin FQ*3*4 (*1; FEBS Lett., 341, 33-38, 1994) (*2; FEBS Lett., *347, 284-288, 1994) (*3; Nature, 377, 532-535, 1995) (*4; Science, 270, 792-794, 1995).
The amino acid sequence of nociceptin is similar to that of Dynorphin A which is an endogenous opioid peptide. Dynorphin A is a κ receptor agonist showing analgesic effect, but binds weakly with ORL-1 receptor and is said to have no activity*5. Nociceptin binds extremely weakly with an opioid receptor*6, and algesia tests including hot plate test*7 using mouse, scratching of lower abdomen with both hindlimbs of mouse, biting and licking of both hindlimbs (SBL) behavior induction test*8 and the like have revealed its promoting action on transmission of pain information. These reports taught that nociceptin and ORL-1 receptor had specific affinity for each other, and nociceptin was a peptide that induced or amplified pain, conversely from the case of opioid peptide. The study of action mechanism thereof is underway. (*5; Eur. J. Pharmacol., 321, 97, 1997) (*6; J. Biol. Chem., 271, 23642, 1996) (*7; Anesthesia, 45, 1060-1066, 1996) (*8; 18th Analgesic Opioid Peptide Symposium Abstract, 11-14, 1997).
ORL-1 receptor has been reported to express more in the central nerve system, such as cerebral cortex, hypothalamus, spinal cord and the like*9, and nociceptin has been shown to be distributed more on the surface layer of dorsicornu where primary pain afferent fiber terminates*10, and algesia transmission of nociceptin is considered to be mainly through central nerve system (*9; J. Neurochemistry, 64, 34-40, 1995) (*10; Neuro Report 7, 3021-3025, 1996).
It has been also reported that administration of nociceptin induces nociceptive hypersensitivity (hyperalgesia*3*4, allodynia*11) and that it amplifies excitatory stimulus by heat and tactile (*11; Molecular Brain Research, 43, 96-104, 1996).
Under the circumstances, substances reported to exhibit a nociceptin antagonistic action are only nociceptin-like polypeptide and naloxone benzoylhydrazone which is a κ receptor antagonist having a morphine-like structure, both of which having ORL-1 receptor affinity, and a pharmaceutical agent having specific antagonistic action on ORL-1 receptor has not been developed.
Known analgesic having a quinoline skeleton includes opioid or anesthetic antagonist analgesic [Japanese Patent Unexamined Publication No. 63-264460 (EP 277794; BOC Inc.)], analgesic having a different action mechanism [Japanese Patent Unexamined Publication No. 62-503030 (U.S. Pat. No. 5,104,884; Alkaloida Vegyeszeti Gyar, antifungal action), WO96/13485 (EP 807105; Fujisawa Pharmaceutical Industries, Ltd., bradykinin antagonist), WO96/11930 (Smithkline beecham P.L.C., serotonin receptor antagonist), Japanese Patent Unexamined Publication No. 59-210084 (U.S. Pat. No. 4,839,366; Chiesi Farmaceutici S.p.A., prostaglandin synthesis inhibition), Japanese Patent Unexamined Publication No. 54-73784 (U.S. Pat. No. 4,293,549; Leo Pharmaceutical Products Limited A/S), FR 1557928 and FR 1543405 (M. Robert ARIES) and the like. These do not include a compound having the structure of the inventive compound, nor do they disclose an action on nociceptin or ORL-1 receptor as in the present invention.
Compounds having a quinoline skeleton structurally similar to that in the inventive compound and which can be used for effects other than analgesic effect are shown in DE 831100 and DE 947552 (anti-blood parasite agent), WO97/14681 (therapeutic agent of bone metabolism abnormality), Japanese Patent Unexamined Publication No. 63-99069 (U.S. Pat. No. 4,753,951; antipsychotic agent), Japanese Patent Unexamined Publication No. 2-167265 (U.S. Pat. No. 5,019,574; psychoneurotic function improving agent), Journal of American Chemistry Society (76, 3703-3708, 1956) (antibacterial agent), HU34479 {disclosure of quinoline skeleton as a synthetic intermediate for imidazo[4,5-c]quinoline derivative (analgesic)} and the like, though none of which discloses effectiveness as an analgesic.